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505(b)(2) Prodrug Fails Phase III Study

Posted by: Ken Phelps

Published on: May 28, 2013

Development of drugs for new indications entails more risk of failure than simply changing formulations. Just ask XenoPort, which announced May 19th that its prodrug of R-baclofen, arbaclofen placarbil, failed to show efficacy in a Phase III clinical trial. Arbaclofen placarbil was being studied for multiple sclerosis-related spasticity. Racemic baclofen, now generic, is indicated for treating muscle spasms, so it doesn’t seem to be a stretch to believe that it would be efficacious . XenoPort based the prodrug on the active enantiomer, R-baclofen. The prodrug approach was used to overcome some limitations of baclofen. According to an abstract of a non-clinical pharmacokientic study, baclofen has

“a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter.”

Interestingly, this non-clinical study demonstrated that in rats, dogs and monkeys, the prodrug was “rapidly converted to R-baclofen” and that “exposure to intact prodrug was low”. Phase 1 human studies were reported:

“…included a total of over 250 healthy volunteers. The results of these Phase 1 clinical trials indicated that AP was well absorbed and rapidly converted to the R isomer of baclofen. Exposure to the intact Transported Prodrug was low compared to the level of R-baclofen produced at all dose levels. Comparison of these data with historical pharmacokinetic data for racemic baclofen suggests that AP taken twice a day should be associated with a decreased peak-to-trough ratio of R-baclofen blood levels over 24 hours compared to racemic baclofen dosed three or four times a day.”

This prodrug profile is one which the FDA considers eligible to be a pk-program-only if it was being developed for an approved indication. As stated before, baclofen is used to treat MS-induced spasticity, so it unknown why this phase 3 trial failed. I could not find any reports of a Phase 2 trial in MS-related spasticity; XenoPort has conducted Phase 2 trials in spinal cord injury and patients with GERD.

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